Prospective study of renal function in HIV-infected pediatric patients receiving tenofovir-containing HAART regimens
Soler-Palacín, Perea,*; Melendo, Susanaa,*; Noguera-Julian, Antonib; Fortuny, Claudiab; Navarro, María Lc; Mellado, María Jd; Garcia, Lourdese; Uriona, Soniaf; Martín-Nalda, Andreaa; Figueras, Concepcióa
aPediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron University Hospital, Spain
bInfectious Diseases Unit, Pediatric Department, Sant Joan de Déu Hospital-Universitat de Barcelona, Barcelona, Spain
cPediatric Infectious Diseases Unit, Gregorio Marañon University General Hospital, Spain
dPediatric Infectious and Tropical Diseases Unit, Carlos III Hospital, Madrid, Spain
ePediatric Department, Hospital de Mataró, Mataró, Spain
fPreventive Medicine Department, Vall d'Hebron University Hospital, Barcelona, Spain.
*These two authors contributed equally to this work.
Received 1 July, 2010
Revised 6 September, 2010
Accepted 23 September, 2010
Correspondence to Pere Soler-Palacin, MD, Pediatric Infectious Diseases and Immunodeficiencies Unit, Vall d'Hebron University Hospital, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain. Tel: +34 93 489 3140; fax: +34 93 489 3039; e-mail: email@example.com, firstname.lastname@example.org
Aim: To describe the impact of tenofovir disoproxil fumarate (TDF) use on renal function in HIV-infected pediatric patients.
Design: It is a prospective, multicenter study. The setting consisted of five third-level pediatric hospitals in Spain. The study was conducted on patients aged 18 years and younger who had received TDF for at least 6 months. The intervention was based on the study of renal function parameters by urine and serum analyses. The main outcome measures were renal function results following at least 6 months of TDF therapy.
Results: Forty patients were included (32 were white and 26 were diagnosed with AIDS). Median (range) duration of TDF treatment was 77 months (16–143). There were no significant changes in the estimated creatinine clearance. Urine osmolality was abnormal in eight of 37 patients, a decrease in tubular phosphate absorption was documented in 28 of 38 patients, and 33 of 37 patients had proteinuria. A statistically significant decrease in serum phosphate and potassium concentrations was observed during treatment (P = 0.005 and P = 0.003, respectively), as well as a significant relationship between final phosphate concentration and tubular phosphate absorption (P = 0.010). A negative correlation was found between phosphate concentration and time on TDF.
Conclusions: TDF use showed a significant association with renal tubular dysfunction in HIV-infected pediatric patients. Periodic assessment of tubular function may be advisable in the follow-up of this population.
Tenofovir disoproxil fumarate (TDF) is the first nucleotide reverse transcriptase inhibitor approved by the Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of HIV infection in adults and has been a first-line antiretroviral drug since 2001 . On the basis of the results of the GS-US-104-0321 study, which will be published at the end of this year, TDF recently received FDA approval for use in pediatric patients aged 12–18 years and weighing more than 35 kg. Moreover, it has been used as salvage therapy in pediatric patients for several years, and various reports support the safety and efficacy of the drug in this population [2–4]. In the pediatric cohort of the Spanish AIDS Research Network (CoRISpe, Cohorte Pediátrica de la Red de Investigación de SIDA), which includes virtually all HIV-infected children in Spain, 87 of the 621 patients included (14%) are receiving or have received TDF at some time (unpublished data).
Since the introduction of HAART and with the advances in our understanding of the disease, survival in HIV-infected children has considerably improved . This has led to lengthier exposure to antiretroviral treatments and an increase in secondary complications, among which is renal toxicity involvement. The spectrum of renal disease in HIV patients has changed in recent years and there are indications of a more prominent role for drug-related adverse effects than nephropathy caused by the virus itself [6–8]. The antiretroviral agents most commonly associated with renal toxicity are lopinavir (LPV), ritonavir (RTV) , didanosine (ddI) , and, more recently, TDF .
Various randomized clinical trials in adults have described a good safety profile for TDF, and very few cases of renal alterations [12–16]. Nonetheless, another randomized study has reported cases of tubular dysfunction  and cohort studies have described renal dysfunction, tubular dysfunction, and diabetes insipidus associated with the use of this drug [12–16]. The importance of renal toxicity caused by TDF is further underlined by reports suggesting that the effects may not be reversible when the drug is discontinued . The pathogenesis of tubular involvement by TDF is unknown. Some authors cite interference with a transporter protein of the tubular epithelial cells, whereas others propose a mechanism of mitochondrial toxicity, as occurs with ddI, or a possible genetic predisposition [19–21]. A recent report has provided evidence of an association between TDF-related renal toxicity and elevated plasma concentrations of the drug .
Little is known about TDF toxicity in pediatric patients. Two randomized studies in children receiving TDF as part of their HAART regimens determined a favorable safety profile for the drug [3,4], whereas in some pediatric cohort studies, cases of renal toxicity have been described, mainly affecting the renal tubules [2,23–25]. A recent case–control study, in which serum renal function markers were determined in patients receiving TDF, suggested a possible association between the use of this drug and development of hypophosphatemia. On the basis of these results, the authors proposed tubular function monitoring in children receiving long-term TDF therapy .
The present prospective, multicenter study investigates possible TDF-related kidney damage in HIV-infected pediatric patients in Spain, by assessment of renal function markers in serum and urine.
Patients and methods
A multicenter cohort study was conducted between 2007 and 2009, with retrospective and prospective data collection in a two-phase design. The study was approved by the Ethics Committee of the coordinating center (Vall d'Hebron University Hospital, Barcelona, Spain) and informed consent for participation was obtained from patients and/or their tutors. Pediatric patients receiving TDF as part of their antiretroviral treatment and followed up in the participating centers were included. In the first phase, the patients' medical records were reviewed and the following information was collected: demographic data, renal function results at the time TDF treatment was started, and concomitant use of other potentially nephrotoxic agents (indinavir, LPV/RTV, ddI, amphotericin, foscarnet, and vancomycin). TDF dosing was adjusted to body weight in all cases. Nineteen patients received TDF in a fixed combination with emtricitabine (Truvada; Gilead Sciences Inc., Foster City, California, USA) and one patient was given TDF in a fixed combination with emtricitabine and efavirenz (Atripla; Bristol-Myers Squibb, New York, New York, USA and Gilead Sciences Inc.).
A second phase was conducted prospectively during the study period. After at least 6 months of TDF treatment, 24-h urine specimens were obtained and renal function was determined in serum and urine, including tubular function testing and 4-h urine osmolality testing. In addition, kidney and bladder ultrasound was performed in all cases to evaluate morphological alterations.
Renal function alterations were defined as any of the following situations: diuresis less than 1 ml/kg per h, creatinine clearance (CrCl) (calculated with the Schwartz formula [26,27]) below the normal values by age and sex for the Spanish pediatric population , fractional sodium excretion more than 2, tubular phosphate reabsorption (TPR) less than 90% or presence of significant urinary calcium or uric acid levels, proteinuria more than 4 mg/m2 per h, urine osmolality abnormalities (defined as less than 800 mOsm/kg after restricted fluid intake), or renal ultrasound alterations. The adverse effects encountered were evaluated with the Division of AIDS (DAIDS) Adverse Events Grading Table (http://rsc.tech-res.com/safetyandpharmacovigilance).
In the descriptive analysis of the data, categorical variables are expressed as the number and percentage, and continuous variables as the median and range. The presence of adverse renal effects (yes/no) was the dependent variable in the bivariate analysis. The χ2 or Fisher's exact test was used to determine relationships with the independent categorical variables, and the Mann–Whitney U test with continuous variables. Associations between the main variable and independent variables were calculated. Statistical analyses were performed with SPSS 13.0 (IBM, Chicago, Illinois, USA). Significance was set at a value of 0.05 or less.
Forty patients aged 18 years or less were included in the study. There were no patients lost to follow-up during the study. The patients' baseline characteristics are shown in Table 1. Median age was 12.5 years (range 8–17 years) at the start of TDF-containing HAART and 15 years (range 11–20 years) when renal function was evaluated. Two patients had previous kidney disease (congenital polycystic disease and left congenital hydronephrosis that had spontaneously resolved at the time of the study).
None of the patients presented serum creatinine concentrations higher than 1 mg/dl at baseline and only two showed a CrCl level lower than normal for their age. Nine patients had received prior nephrotoxic drugs (most commonly indinavir, with five cases).
Median duration of TDF treatment was 77 months (range 16–143). Ten patients received other nephrotoxic antiretroviral drugs together with TDF (LPV/RTV, n = 7, and ddI, n = 3). The ddI–TDF combination was given before 2005 in all patients receiving this treatment.
In the renal function study after at least 6 months of TDF therapy, a decrease in CrCl values (median decrease of 16.5 mg/ml, range 1–100) was observed in 18 patients. Nonetheless, in only four of these patients, CrCl at the end of the study was below normal values (previously documented in two patients at the beginning of the study).
In addition, a TPR decrease was found in 28 of 38 patients [74%, 95% confidence interval (CI) 56.9–86.6%], proteinuria was seen in 33 patients (89%, 95% CI 75–97%), of whom 10 had proteinuria in the nephrotic range, and urine osmolality alterations were documented in eight of the 37 patients studied (22%) (Table 2). None of the patients presented pathologic calciuria and five patients had increased urinary uric acid levels. Only the patient with congenital polycystic disease presented abnormal sonographic findings (increased size and echogenicity of the kidneys). One patient died during the study period of causes unrelated to TDF treatment or renal dysfunction (cytomegalovirus disease resistant to antiviral therapy).
In the study of risk factors associated with glomerular filtration alterations, there were no significant differences regarding the patients' baseline characteristics, including hepatitis C virus infection and other concomitant pathologies.
A significant increase in serum creatinine concentration between the pretreatment and the final determination (P = 0.001) was observed and alterations in urine osmolality occurred more often in patients who had received prior nephrotoxic drugs [P = 0.049 and relative risk (RR) 6.25, 1–35].
A statistically significant decrease in serum phosphate and potassium concentrations was seen along the duration of treatment (P = 0.005 and P = 0.003, respectively) (Table 3), and six patients presented DAIDS grade 1 or 2 serum phosphate decrease. There was no relationship between phosphate concentration at completion of the study and the baseline characteristics or baseline glomerular involvement. In contrast, an association was found between final serum phosphate values and TPR alteration (P = 0.010), together with a negative correlation between serum phosphate concentration and time on TDF treatment (r = −0.48, P = 0.013) (Fig. 1). This latter association was not seen for serum potassium concentration (P = 0.08).
Proteinuria and TPR alteration were not related with significant baseline immunosuppresion (P = 0.61 and P = 0.73, respectively) nor low BMI (P = 0.60 and P = 0.30, respectively).
Patients who additionally received LPV/RTV or ddI did not exhibit more pronounced CrCl decreases or higher serum creatinine levels. There was, however, a statistically significant urine osmolality alteration in patients receiving LPV/RTV together with TDF (P = 0.027 and RR 8.7, 1.4–54). All patients receiving LPV/RTV or ddI showed moderate to severe proteinuria, as well as a lower TPR (Fig. 2).
The use of TDF is not unusual in the pediatric age, particularly in the adolescent population. Currently in Spain, 14% of patients in the CoRISpe cohort have received TDF at some time point as a part of their HAART regimens (unpublished data). The demographic and clinical characteristics of the patients included in our study are similar to those of the CoRISpe patients who received TDF, as well as to those included in previous studies [2,4,8], that is, mainly, adolescents who were given TDF as part of a salvage therapy. Thus, it is likely that the study results would be applicable to the overall population of pediatric patients receiving this drug. The findings of considerable tubular dysfunction observed in our patients do not differ from the results of other studies in children assessing renal toxicity associated with TDF use [2,8,25].
It has been well demonstrated that the specimen of choice to determine the existence of tubular proteinuria is 24-h urine [6,13,29], as we used in this study. Other, simpler methods, including urine reagent strips or the urinary protein/creatinine ratio, used by other authors  are less suitable for this purpose.
Moderate (>4 mg/m2 per h) or severe (>40 mg/m2 per h) proteinuria was detected in 78% of the patients studied, suggesting some degree of glomerular dysfunction in most severe cases. The fact that proteinuria was not measured at baseline in our study precludes establishment of a causal relationship with TDF use. Nonetheless, the progressive tubular dysfunction observed following initiation of TDF suggests an etiological role for the drug. The association between proteinuria and TDF use in HIV-infected patients has not been well established. In this regard, a percentage of proteinuria similar to that recorded in our cohort has been described for adult HIV-infected patients, although no relationship with the different antiretroviral regimens could be established . In other studies, however, TDF use has been associated with proteinuria in both adults and children [6,31,32]. Papaleo et al.  reported that more than a quarter of patients receiving TDF presented elevated urinary levels of β-2 microglobulin, which normalized upon withdrawal of the drug.
With regard to serum and urinary phosphate concentrations, TPR abnormalities were seen in 90% of patients and six of them showed a DAIDS grade 1 or 2 serum phosphate decrease. Moreover, serum phosphate alterations were significantly related to both TPR changes and time on TDF treatment. In the study by Judd et al. , a difference was seen in the incidence of hypophosphatemia (DAIDS grade 2) between patients on TDF and those who had never received this drug. Along this same line, Izzedine et al. suggested that hypophosphatemia (as well as glucosuria in the absence of hyperglycemia) would be a good marker of tubular toxicity due to TDF . In contrast, other authors contend that moderate, asymptomatic hypophosphatemia is normal in adult HIV-infected patients regardless of the HAART they receive [11,33]. Nonetheless, these studies were performed in adults and follow-up lasted less than 1 year, factors that could explain the differences with respect to our study that had a follow-up of around 6.5 years.
There were no cases of Fanconi syndrome in our series, an uncommon complication recently reported in patients receiving TDF [23,34].
It has been described that TDF-related renal toxicity may increase when the drug is combined with other antiretroviral drugs , particularly with LPV/RTV or ddI. Most patients in our cohort had been treated with several antiretroviral regimens, although few of them received TDF combined with LPV/RTV or ddI. The TDF–LPV/RTV combination was associated with moderate to severe proteinuria and TPR decrease, although the differences with respect to the remaining patients were not significant, possibly because of the small sample size. A significant association was found between urine osmolality alterations and combined use of TDF and LPV/RTV. This finding may be related to an increase in plasma TDF resulting from pharmacokinetic interactions between the two antiretroviral drugs [23,35], a factor that was not investigated in our study.
Considering that the peak in bone mineral density occurring in adolescence is inversely related with the risk of osteopenia, osteoporosis, and bone fracture in adulthood [36–37], the increased incidence of bone pathology in HIV-infected patients  supports the idea that monitoring calcium–phosphate metabolism in HIV-infected children and adolescents is of particular interest. Furthermore, some authors have found that TDF use is an independent risk factor for developing bone mineral loss . In an experimental animal study, Van Rompay et al.  demonstrated an association between prolonged, high-dose TDF administration and hypophosphatemia and development of osteomalacia.
The main limitation of our study is the relatively small sample size, although the comparability of the patients included with those receiving TDF in the CoRISpe cohort and other pediatric studies evaluating TDF-associated renal toxicity confers greater validity to the results obtained. In addition, because baseline evaluation of tubular function was not performed, it was not possible to establish a causal relationship in the results found. In any case, the documentation of significant proteinuria in a high percentage of patients and the correlation between phosphate levels and tubular dysfunction, as well as the optimum sample studied (24-h urine), lead us to suggest that TDF played an important role in the renal alterations described.
In conclusion, this is the first study prospectively assessing renal function in depth, including analysis of tubular function, in pediatric patients undergoing long-term TDF treatment. On the basis of the results obtained, we believe that periodic monitoring of tubular function should be included in the routine follow-up of these patients. Further investigation is needed to determine the contribution of TDF to alterations in calcium–phosphate metabolism and its potential association with bone metabolism alterations.
This study was funded in part by the AIDS Research Network (RIS, Red de Investigación en SIDA) and the Foundation for AIDS Research and Prevention in Spain (FIPSE, Fundación para la Investigación y la Prevención del SIDA en España; 240813/09).
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kidney; pediatrics; reverse transcriptase inhibitors; tenofovir disoproxil fumarate; toxicity
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